INTASYL self-delivery technology

Sponsor(s)

Triton Funds https://www.tritonfunds.com/

Partnerships

	Glycostem Ltd. https://www.glycostem.com/
	Helmholtz Zentrum München https://www.helmholtz-munich.de/
	Medigene AG https://medigene.com/

Type of technology

Chemically modified siRNA for self-delivery

Administration route

Intratumoral, Intra-vitreal

Development state and regulatory approval

PH-762

Phase I

FDA has cleared the IND application for PH-762

Description

INTASYL™ Technology is a proprietary self-delivering RNA interference (sd-rxRNA®) platform designed for precise gene silencing in immuno-oncology. Unlike traditional RNAi therapies, INTASYL allows direct cellular uptake without requiring complex delivery systems. Engineered for immune cells, it enhances anti-tumor responses while ensuring safety, stability, and efficiency. The sd-rxRNA molecules are chemically modified with hydrophobic and hydrophilic elements, enabling passive diffusion into cells. These modifications also provide stability and resist disintegration.

Technology highlight

1. Chemically modified siRNA structure and self-delivery system 2. Cellular uptake mechanism via direct membrane penetration 3. Intracellular processing and RNA-induced silencing complex (RISC) Activation 4. Gene silencing and Immuno-oncology applications 5. Target specificity

Technology main components

Chemically modified siRNA

Information on the raw materials sourcing, availability and anticipated price

Not provided

Delivery device(s)

No delivery device

API desired features

Proteins

INTASYL self-delivery technology utilizes siRNA to specifically target and silence a range of immuno-oncology proteins, including PD-1, BRD4, CTLA4, TIGIT, LAG3, TIM3, CBLB, SHP-1, STAT-3, MDM2, ADORA2, MMP-1, CD96, CISH, CSK, DGKα, DGKζ, DNMT3A, HK2, IL-6, KLRC1, PD-L1, PRDM, PTEN, TBX21, TET2, and other related proteins involved in immune regulation and tumor evasion. Additionally, it targets dermatology-related proteins such as CTGF, COX2, TGFB1, TGFB2, SPP1, TYR, and MMP1, as well as BRD4, contributing to therapeutic strategies in both immuno-oncology and dermatological conditions.

Additional solubility data

Not provided

Additional stability data

Not provided

API loading: Maximum drug quantity to be loaded

75-90 wt%

API co-administration

2 different APIs : Two APIs should target different genes simultaneously

LogP

Not provided

Scale-up prospects

Not provided

Tentative equipment list for manufacturing

Mermade 12 DNA/RNA Synthesizer

Manufacturing

Manufacturing Process of INTASYL (cGMP): 1. Oligonucleotide Synthesis (via Mermade 12 DNA/RNA Synthesizer) 2. Cleavage and Deprotection 3. Purification (via ion exchange chromatography) 4. Sense Strand Purification 5. Desalting and Concentration 6. Analysis by HPLC and ESI-MS.

Specific analytical instrument required for characterization of formulation

1. HPLC analysis on a Shimadzu Prominence system. 2. Electrospray Ionization Mass Spectrometry (ESI-MS) analysis using Promass Deconvolution for Xcalibur.

PHIO-762-2301

Identifier

NCT06014086

Link

https://clinicaltrials.gov/study/NCT06014086

Phase

Phase I

Status

Recruiting

Sponsor

Phio Pharmaceuticals Inc.

More details

The goal of this clinical trial is to evaluate the safety and tolerability of intratumoral injections of PH-762 in squamous cell carcinoma, melanoma, or Merkel cell carcinomas of the skin, to understand what the body does to the PH-762, and to observe how the tumor responds to the drug. Participants will receive four injections of PH-762 at weekly intervals, into a single tumor, followed by surgical removal of the tumor approximately two weeks later.

Purpose

Intratumoral PH-762 for Cutaneous Carcinoma

Interventions

Intervention 1

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2023-11-07

Anticipated Date of Last Follow-up
2025-01-24

Estimated Primary Completion Date
2025-06-01

Estimated Completion Date
2025-09-01

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Key Inclusion Criteria: * Histologically confirmed cutaneous squamous cell carcinoma (cSCC), melanoma, or Merkel cell carcinoma, meeting one of the following criteria: * cSCC, resectable local tumors: must be Stage II or lower, amenable to curative resection and in a location where acceptable surgical margins are anticipated * cSCC, unresectable local tumors: must be Stage II or lower, tumor has been unresponsive to prior radiation therapy or is not a candidate for curative radiation therapy * cSCC, metastatic disease: disease has progressed during or following prior checkpoint inhibitor therapy (anti-PD-1 or anti-PD-L1 antibody) * Melanoma, metastatic disease: Stage IV disease with a cutaneous lesion that has progressed during or following checkpoint inhibitor therapy.

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

30

Allocation

Not provided

Intervention model

Single group assignment

Intervention model description

Not provided

Masking

Open label

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key results

RXI-109-1501

Identifier

NCT02599064

Link

https://clinicaltrials.gov/study/NCT02599064

Phase

Phase I/II

Status

Unknown status

Sponsor

RXi Pharmaceuticals, Corp.

More details

This study is designed to evaluate the safety, tolerability and clinical activity of RXI-109 administered by intravitreal injection to reduce the progression of subretinal fibrosis in subjects with advanced neovascular age-related macular degeneration (NVAMD).

Purpose

Evaluating RXI-109 to Reduce the Progression of Subretinal Fibrosis in Subjects With NVAMD

Interventions

Intervention 1

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2015-11-01

Anticipated Date of Last Follow-up
2018-02-22

Estimated Primary Completion Date
2018-04-01

Estimated Completion Date
2018-05-01

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Inclusion Criteria: * Subjects presenting with advanced NVAMD in the study eye with BCVA ≤20/100 potentially due to subretinal fibrosis involving the fovea * BCVA ≥20/800 in the contralateral eye and better than the study eye * ≥50 years of age * Subfoveal choroidal neovascularization (CNV) of any type Exclusion Criteria: * Presence of other causes of CNV including pathologic myopia, ocular histoplasmosis syndrome, angioid streaks, choroidal rupture, and multifocal choroiditis * Evidence of inflammation (Grade 1 or higher) in the anterior or posterior chamber.

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

Not provided

Allocation

Not provided

Intervention model

Single group assignment

Intervention model description

Not provided

Masking

Open label

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key results

Proprietary excipients used

No proprietary excipient used

Novel excipients or existing excipients at a concentration above Inactive Ingredients Database (IID) for the specified route of administration

No novel excipient or existing excipient used

Residual solvents used

No residual solvent used

Other features of the technology

Not provided

Release properties

When the INSTACYL formulation is administered locally, i.e., intratumorally, the chemically modified siRNA undergoes spontaneous cellular uptake due to the interaction of the lipophilic functional group (e.g., sterol group) with the cell membrane. Thus, the cellular uptake of INSTACYL does not require facilitated transport systems or carriers.

Injectability

INSTACYL formulation is designed for intratumoral and intravitreal route of adminstration.

Safety

The INSTACYL products were well tolerated in the clinical phase 1 studies. One of such study on PH-762 once weekly (for 4 weeks) indicate that there was no No dose-limiting toxicities or clinically significant treatment-emergent adverse effects have been reported.

Stability

Not provided

Storage conditions and cold-chain related features

Not provided

Therapeutic area(s)

Use case(s)

Use of technology

Description

Chemically modified oligonucleotides

Brief description

The disclosure relates, in some aspects, to methods and compositions for production of immunogenic compositions. In some embodiments, the disclosure provides host cells which have been treated ex vivo with one or more oligonucleotide agents capable of controlling and/or reducing the differentiation of the host cell. In some embodiments, compositions and methods described by the disclosure are useful as immunogenic modulators for treating cancer.

Representative patent

AU2018313149B2

Category

Not provided

Patent holder

Phio Pharmaceuticals Corp

Exclusivity

Not provided

Expiration date

August 7, 2038

Status

Active

Description

Reduced size self-delivering RNAi compounds

Brief description

A method for delivering a nucleic acid to a remote target tissue in a subject in need thereof, comprising systemically administering to the subject an sd-rxRNA® in an effective amount to promote RNA interference by the sd-rxRNA® in the remote target tissue, wherein the sd-rxRNA® comprises a guide strand and a passenger strand, wherein the sd-rxRNA® includes a double-stranded region and a single stranded region wherein the double stranded region is from 8-15 nucleotides long, wherein the single stranded region is at the 3′ end of the guide strand and is 4-12 nucleotides long, wherein the single stranded region contains 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 phosphorothioate modifications, wherein at least 40% of the nucleotides of the sd-rxRNA® are modified, and wherein at least two Us.

Representative patent

US10240149B2

Category

Not provided

Patent holder

Phio Pharmaceuticals Corp

Exclusivity

Not provided

Expiration date

March 24, 2031

Status

Active

Description

Phagocytic cell delivery of RNAI

Brief description

The present invention provides a particulate delivery system for delivering an RNAi construct to phagocytic cells such as macrophages, comprising various configurations of a complex comprising a phagocytic cell-targeting moiety and an RNAi construct. The invention further provides methods of making the delivery system, and their uses, such as treating phagocytic cell-associated disease conditions.

Representative patent

US8815818B2

Category

Not provided

Patent holder

Phio Pharmaceuticals Corp

Exclusivity

Not provided

Expiration date

August 16, 2029

Status

Active

Publications

<p><span style="color: rgb(33, 33, 33);">Maxwell, M., Holton, K., Looby, R. J., Byrne, M., &amp; Cardia, J. (2024). Self-Delivering RNAi Compounds for Reduction of Hyperpigmentation.&nbsp;</span><em style="color: rgb(33, 33, 33);">Clinical, cosmetic and investigational dermatology</em><span style="color: rgb(33, 33, 33);">,&nbsp;</span><em style="color: rgb(33, 33, 33);">17</em><span style="color: rgb(33, 33, 33);">, 3033–3044. </span><a href="https://doi.org/10.2147/CCID.S498987" rel="noopener noreferrer" target="_blank" style="color: rgb(33, 33, 33);">https://doi.org/10.2147/CCID.S498987</a></p>

Purpose: Abnormal melanin synthesis causes hyperpigmentation disorders like melasma and lentigines, impacting psychological well-being. RNA interference (RNAi) uses small RNA molecules to inhibit gene expression by targeting specific mRNA, silencing genes involved in undesirable cellular functions. This study assessed INTASYL compounds, self-delivering RNAi molecules, designed to target and reduce tyrosinase gene expression to decrease pigmentation.

Methods: 36 INTASYL compounds were designed to target and reduce TYR gene expression and tested in a screening assay. RXI-231, the lead compound, was tested in normal human epithelial melanocytes and the MelanoDerm™ model, a 3D reconstituted human epidermal culture. RXI-231 was evaluated for its ability to reduce tyrosinase mRNA expression, in vitro dopachrome formation, and melanin content. Penetration of fluorescently labeled INTASYL compounds through the stratum corneum into the epidermis was tested in cultured porcine skin explants using a DermaPen® microneedle device and a proprietary mixture of penetration enhancers. RXI-231 was also tested for skin irritation in the MatTek EpiDerm™ model to determine its non-irritant profile.

Results: RXI-231 significantly reduced tyrosinase mRNA expression, dopachrome formation, and melanin content in both normal human melanocytes and the MelanoDerm model. Application of INTASYL compounds every other day visibly reduced pigmentation in the 3D epidermal cultures. Penetration studies showed efficient delivery into the epidermis, overcoming the stratum corneum barrier. RXI-231 showed no irritation, with viability above 50% in the MatTek EpiDerm model, confirming its non-irritant profile.

<p><span style="color: rgb(33, 33, 33);">Cuiffo, B., Maxwell, M., Yan, D., Guemiri, R., Boone, A., Bellet, D., Rivest, B., Cardia, J., Robert, C., &amp; Fricker, S. P. (2024). Self-delivering RNAi immunotherapeutic PH-762 silences PD-1 to generate local and abscopal antitumor efficacy.&nbsp;</span><em style="color: rgb(33, 33, 33);">Frontiers in immunology</em><span style="color: rgb(33, 33, 33);">,&nbsp;</span><em style="color: rgb(33, 33, 33);">15</em><span style="color: rgb(33, 33, 33);">, 1501679. </span><a href="https://doi.org/10.3389/fimmu.2024.1501679" rel="noopener noreferrer" target="_blank" style="color: rgb(33, 33, 33);">https://doi.org/10.3389/fimmu.2024.1501679</a></p>

Objective: Immunotherapeutic inhibition of PD-1 by systemically administered monoclonal antibodies is widely used in cancer treatment, but it may cause severe immune-related adverse events (irSAEs). Neoadjuvant PD-1 inhibition before surgery has shown promise in reducing recurrence by stimulating durable antitumor immunity. Local intratumoral (IT) immunotherapy is a potential strategy to minimize irSAEs, but antibodies have limited tumor penetration, making them less suitable for this approach. Therapeutic self-delivering RNAi (INTASYL) is an emerging modality well-suited for neoadjuvant immunotherapy. This study presents preclinical proof-of-concept for PH-762, an INTASYL designed to silence PD-1, currently in clinical development for advanced cutaneous malignancies (ClinicalTrials.gov#NCT06014086).

Methods and analysis: PH-762 pharmacology was characterized in vitro, and in vivo antitumor efficacy was evaluated using a murine analogue (mPH-762) in syngeneic tumor models with varying PD-1 responsiveness. Bilateral Hepa1-6 models assessed abscopal effects of local treatment. Ex vivo analyses explored mechanisms of direct and abscopal efficacy.

Results: PH-762 was rapidly internalized by human T cells, silencing PD-1 mRNA and decreasing PD-1 surface protein, enhancing TCR-stimulated IFN-γ and CXCL10 secretion. In vivo, IT mPH-762 provided robust antitumor efficacy, local and lymphatic biodistribution, and was well tolerated. Ex vivo analyses revealed that IT mPH-762 depleted PD-1 protein, promoted leukocyte and T cell infiltration, and correlated with tumor control. IT mPH-762 also demonstrated efficacy against untreated distal tumors (abscopal effect) by priming systemic antitumor immunity.

Additional documents

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Useful links

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